The objective of our research is to understand the mechanisms of progesterone receptor (PR) in suppressing cervical cancer. Although human papillomavirus (HPV) is required for the malignancy, it is not sufficient and other non-viral factors are implicated in cervical carcinogenesis. Roles of female hormones, estrogen and progesterone have been underexplored due to lack of a relevant model system. These hormones function through their cognate receptors, estrogen receptor a (ERa) and progesterone receptor (PR). Studies using HPV transgenic mouse model have revealed that estrogen and stromal ERa are indispensable for progression of cervical neoplastic disease. Our hypothesis is that PR is a ligand-dependent tumor suppressor in cervical cancer. Using the HPV transgenic mouse model and our new orthotopic xenograft mouse model, three specific aims will be addressed in this study: (1) it will be determined whether epithelial PR and/or stromal PR suppresses cervical cancer; (2) genes and pathways that are regulated by PR and relevant to cervical cancer suppression will be determined by microarray analyses; and (3) the efficacy of PR agonists in treating cervical cancer will be evaluated. Epithelium-specific or stroma-specific Cre mice will be used to delete PR in a cell type-specific manner. Also employed will be orthotopic xenograft mouse model in which human cervical cancer cells (PR+ or PR-) will be injected to cervix of immunocompromised mice. HPV vaccines hold promise in reducing cervical cancer incidence; however, they are not effective for all high-risk HPV types and women who are already infected. Current therapies are not effective for high-grade cervical diseases, leading to ~250,000 death every year worldwide. These studies will provide further understanding of pathogenesis of cervical cancer and thereby facilitate the development of a new effective therapy for the disease.